DESCRIPTION: The mammalian nervous system is composed of a multitude of distinct neuronal subtypes, each with its own phenotype and differential sensitivity to degenerative disease. Although some specific neuronal types can be isolated from intact rodent embryos or engineered from stem cells for translational studies, these approaches are time-consuming and many neuronal subtypes are inaccessible. Transcription factor-mediated reprogramming might provide a more direct route to the generation of neurons for disease modeling and regenerative medicine, but it is currently unclear if this approach can be used to create cells with translationl utility. Here, we propose to identify a set of transcription factors sufficient to convert fibroblats into functional spinal motor neurons. We will characterize the reprogramming process and examine the molecular and functional properties of the resulting motor neurons in order to determine their therapeutic potential. These studies will provide an accessible source of patient-specific motor neurons for the study of neurodegenerative disease, demonstrate that specific adult cell types can be directly generated from somatic cells using defined factors, and mechanistically dissect the defined-factor reprogramming process. PUBLIC HEALTH RELEVANCE: The mammalian nervous system is composed of a multitude of distinct neuronal subtypes, each with its own phenotype and differential sensitivity to degenerative disease and although some specific neuronal types can be isolated from intact rodent embryos or engineered from stem cells for translational studies, these approaches are time-consuming and many neuronal subtypes are inaccessible. The goal of these studies is to identify a small group of defined transcription factors can convert fibroblasts directly into motor neurons, thereby enabling the rapid generation of these cells for therapeutic use. More broadly, these studies will investigate the potential of using defined-factor reprogramming to create specific adult cell types with translational utility. )